Abstract
Increased beta-band oscillatory activity in the basal ganglia network is associated with Parkinsonian motor symptoms and is suppressed with medication and deep brain stimulation (DBS). The origins of the beta-band oscillations, however, remains unclear with both intrinsic oscillations arising within the subthalamic nucleus (STN)—external globus pallidus (GPe) network and exogenous beta-activity, originating outside the network, proposed as potential sources of the pathological activity. The aim of this study was to explore the relative contribution of autonomous oscillations and exogenous oscillatory inputs in the generation of pathological oscillatory activity in a biophysically detailed model of the parkinsonian STN-GPe network. The network model accounts for the integration of synaptic currents and their interaction with intrinsic membrane currents in dendritic structures within the STN and GPe. The model was used to investigate the development of beta-band synchrony and bursting within the STN-GPe network by changing the balance of excitation and inhibition in both nuclei, and by adding exogenous oscillatory inputs with varying phase relationships through the hyperdirect cortico-subthalamic and indirect striato-pallidal pathways. The model showed an intrinsic susceptibility to beta-band oscillations that was manifest in weak autonomously generated oscillations within the STN-GPe network and in selective amplification of exogenous beta-band synaptic inputs near the network's endogenous oscillation frequency. The frequency at which this resonance peak occurred was determined by the net level of excitatory drive to the network. Intrinsic or endogenously generated oscillations were too weak to support a pacemaker role for the STN-GPe network, however, they were considerably amplified by sparse cortical beta inputs and were further amplified by striatal beta inputs that promoted anti-phase firing of the cortex and GPe, resulting in maximum transient inhibition of STN neurons. The model elucidates a mechanism of cortical patterning of the STN-GPe network through feedback inhibition whereby intrinsic susceptibility to beta-band oscillations can lead to phase locked spiking under parkinsonian conditions. These results point to resonance of endogenous oscillations with exogenous patterning of the STN-GPe network as a mechanism of pathological synchronization, and a role for the pallido-striatal feedback loop in amplifying beta oscillations.
Highlights
Pathological oscillations in the basal ganglia-thalamocortical (BGTC) network have long been implicated in the motor symptoms of Parkinson’s disease
The subthalamic nucleus (STN)-GPe pacemaker hypothesis was first investigated by modeling cortical inputs to the STN as Poisson spike generators without any periodic or oscillatory component
Cortical patterning of neural activity in the STN-GPe network via the hyperdirect pathway was investigated by modeling cortical input to the STN inputs as periodically bursting spike trains
Summary
Pathological oscillations in the basal ganglia-thalamocortical (BGTC) network have long been implicated in the motor symptoms of Parkinson’s disease. Different models have placed the origin of beta and sub-beta band oscillations in the STN-GPe network (Terman et al, 2002; Gillies and Willshaw, 2007; Holgado et al, 2010; Pavlides et al, 2012), in cortical and thalamo-cortical circuits (Pavlides et al, 2015; Sherman et al, 2016; Liu et al, 2017; Reis et al, 2019), in striatal or pallidostriatal circuits (McCarthy et al, 2011; Corbit et al, 2016), or in the full BGTC loop (Leblois, 2006; Kang and Lowery, 2013; Pavlides et al, 2015; Kumaravelu et al, 2016). These models show that under many conditions the network is prone to oscillate, through intrinsic pacemaking or susceptibility to an extrinsic rhythm
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